PRC projects will develop and test selective and indicated prevention strategies across three domains of vulnerability to major depression in later life: changes in physical health (especially those that entail loss of independence), depletion of psychosocial resources, and increasing cognitive impairments. Each of the three pilot prevention trials has been designed to address multiple areas of vulnerability. The PRC methods development project will utilize data from all three prevention trials to model longitudinal trajectories of risk (clinical, psychosocial, biological) in the service of (1) developing on-target (personalized), on-time risk reduction strategies and (2) better understanding moderators and mediators of depression prevention in older adults. The methods development work in dynamic (that is, longitudinal and updatable) risk assessment will be fed back to the prevention pilot studies as they developing into ROIs, allowing them to test for ways of enhancing the efficiency and impact of risk-reduction strategies in vulnerable older adults. The three prevention trials encompass a range of learning-based interventions that are structured but tailored to be responsive to individual participant needs: enhancing problem solving skills, improving sleep quality, exercise, CBT-based approaches to pain, and conjointly intervening with both care recipient and caregiver. The ensemble of PRC projects address the mandate in the NIMH Strategic Plan (2.3) to develop and test innovative interventions to reduce risk and positively alter trajectories of illness. Two of the PRC study PIs qualify for the NIH designation of Early Stage Investigator: Karp and Thompson. As noted in the Administrative Unit of the Operations Core (Page 128), the Center will also fund competitive, peer-reviewed seed money and small awards as a further strategy for supporting research career development activity in depression prevention. We will target projects from Early Stage Investigators that propose to test biological mediators and moderators of depression prevention. For example, projects testing depression prophylaxis via exercise in the post-stroke patient and protecting sleep in patients exposed to depressogenic interventions such as interferon alpha, exemplify opportunities to further examine psychobiological mechanisms of depression prophylaxis.